In recent years great advances in medical technology have produced man made materials that make direct contact with human blood. For example, medical devices must be used in temporarily conducting the blood out of the body or used as substituted artificial organs in the body thereby necessitating the devices making direct contact with blood. Such materials include by way of example, monitoring tubes, artificial kidneys, heart valves, blood by-pass tubes and dialysis membranes.
The present state of medical technology indicates that polymers, both natural and synthetic, particularly certain synthetic plastics, have come into prominence as preferred materials for prosthetic devices. It is also known that upon contact with such materials, the blood easily coagulates and forms a thrombus or a clot on the surface of such materials. The thrombus or clot creates the serious risk of blood current blockage or, alternatively, moves along with the blood flow to cause equally dangerous complications such as pulmonary thrombosis, cerebral thrombosis or myocardial infarction.
In the use of blood contacting medical devices it has always been conventional medical practice to prevent thrombus formation by systematically administering to a patient an anticoagulant agent such as heparin, coumarine, and similar compositions. However, direct and systematic administration of these anti-coagulants also increases the risks of bleeding in a subject.
Heparin is the most well known anticoagulant and a polysaccharide not having a uniform molecular structure. It is generally considered a mixture of polymers of varying size and slight differences exist between the polymers and in the individual sugars within a particular polymer grouping. It is current expert opinion that heparin is composed of alternating derivatives of D-glycocyamine (N-sulfated or N-acetylated) and uranic acid (L-iduronic acid with varying sulfate or D-glucuronic acid) joined by glycosidic linkages.
In an effort to counteract thrombogenicity and engendered bleeding, caused by direct administration of heparin, many researchers developed methods of attaching and binding heparin in the form of a coating to the walls of medical articles. Dr. Vincent Gott made the original advance in the preparation of non-thrombogenic materials by treating a graphite plastic surface with benzalkonium chloride and then with heparin. Materials treated in this way were non-thrombogenic in vitro for prolonged periods of time. Further developments followed. Two patents issued to Ericksson et al U.S. Pat. Nos. 3,810,781 and 4,118,485, where a medical article is rendered non-thrombogenic by applying a heparin coating prepared by providing a dialdehyde. Another patent issued to Eriksson et al, U.S. Pat. No. 4,265,927, issued on May 5, 1981, teaches reacting a charged surface with a colloidal aqueous solution of a cationic surface active agent and heparin. The surface active agent of choice is specifically mentioned as one of a primary amine type.
While such medical research has resulted in improved stabilization of the heparinized surface, the covalent bonding which takes place with the stabilizing dialdehyde results in reduction of the physiological activity of the heparin. Additionally, such a procedure is complicated in that many steps are involved and, consequently, is relatively costly.
One presently available heparin complex used to treat blood contacting surfaces is formed from benzalkonium chloride. This available complex is actually a mixture of alkylbenzyldimethylammonium chloride of the general formula, [C.sub.6 H.sub.5 CH.sub.2 N (CH.sub.3).sub.2 R]Cl, in which R represents a mixture of alkyls, including all or some of the groups comprising C.sub.8 and greater, with C.sub.12, C.sub.14 and C.sub.16 comprising the major portion. Generally, the composition breaks down to more than 20% C.sub.14, more than 40%, C.sub.12 and a less than 30% mixture of C.sub.8, C.sub.10 and C.sub.16. The use of benzalkonium chloride is taught in U.S. Pat. No. 3,522,346, issued to Chang on July 28, 1970; and in the articles "Semipermeable Aqueous Microcapsules", Chang et al, Canadian Journal of Physiology and Pharmacology, Vol. 45, 1967, Pages 705-715; and "A Simple Non-thrombogenic Coating", Amplatz, MD, Investigative Radiology, Vol. 6, No. 4, July-August 1971, Pages 280-289. While the use of benzalkonium chloride/heparin complex coatings on medical articles has been effective, especially for short duration applications, they still demonstrate limited stability.
The binding of heparin onto a plastic polymer surface in a fully stable way has presented considerable difficulties. One major disadvantage with plastic materials coated with currently available heparin-benzalkonium complexes is that these coating complexes are unstable and subject to desorption or leaching. Consequently, in contact with biological fluids such coating can lose up to one half of the heparin content in a period of 20 minutes. The offered explanation for this phenomena is that the ionic bonding of the anionic heparin to the cationic organic quaternary ammonium groups in the plastic surface is so unstable that heparin is continuously lost with fluid flow. Only short term applications involving blood contact of short duration can be carried out with such unstable heparinized surfaces.
Other investigators have suggested using additional types of ammonium salts which are complexed with heparin. A group of surface active agents was suggested in U.S. Pat. No. 3,717,502, issued to Masuhara et al on Feb. 20, 1973. This list broadly includes dimethyl alkylbenzyl ammonium chloride, benzyldimethyl-2-[2-(p-1,1,3,4-tetramethylbutyl phenoxy) ethoxyl]ammonium chloride, alkyl-trimethylammonium chloride, dilauryldimethyammonium chloride or the like. Alkyl-ammonium salts were suggested in U.S. Pat. Nos. 4,302,368, issued to Dudley, deceased et al on Nov. 24, 1981; and 3,634,123, and in article "A Thrombogenic Index For Blood Contacting Materials", Roohk et al, American Society Artificial Internal Organs, Vol. XXIII, 1977, page 152-161.
As demonstrated above, benzalkonium chloride/heparin complex coatings, while providing adequate biocompatibility, were not sufficiently stable in saline. Other investigators have demonstrated that some alkyl ammonium salts, e.g. tridodecylmethyl ammonium salts, do not inhibit thrombogensis.
Still other investigators have complexed heparin with esters, see U.S. Pat. No. 3,835,112, issued to
Mandiguian et al on Sept. 10, 1974, U.S. Pat. No. 4,440,926, issued to Mandiguian on Apr. 3, 1984 and French Pat. No. 010792 issued on Nov. 20, 1981, to Pharmindustrie. In U.S. Pat. No. 4,326,532, issued to Hammar on Apr. 27, 1982, heparin and chitosan were reacted together to form a non-thrombogenic coating.
Still further investigators have suggested attaching heparin covalently or ionically to polymers, see U.S. Pat. Nos. 4,415,490, issued to Joh on Nov. 15, 1983; 3,853,804, issued to Yen et al on Dec. 10, 1974, 4,350,806, issued to Hagener on Sept. 21, 1982 and Japanese Patent 043041, issued to Toray Industries Inc. on Nov. 4, 1979.
Other attempts of attaching heparin to device surfaces have involved preparing the substrate surface to react with cationic or anionic compounds, e.g. heparin. In U.S. Pat. No. 4,565,740, issued to Golander et al on Jan. 21, 1986 a complex formed by treating the substrate surface with a polymeric cationic surfactant and a dialdehyde could then be subsequently reacted with cationic or anionic compounds, including heparin. U.S. Pat. No. 4,254,180, issued to Kline on Mar. 3, 1981, disclosed a mixture of a resin and colloidal graphite used to form objects. The exposed surface was made heparin recieptive by treatment with a cationic surface active agent. Derivatives of heparin have also been suggested as providing anti-thrombogenic properties. For example, in U.S. Pat. No. 4,331,697, issued to Kudo et al on May 25, 1982, a specific derivative of heparin was disclosed which in the presence of actinic light was applied to the surface of medical devices.
The above references demonstrate the keen interest in developing a heparin, or similar type reagent, biocompatible coating. However, available heparin coatings do not provide adequate saline stability or non-thrombogenic properties. Against this background it is important to find new heparin coating compositions which optimize stability, particularly in saline, and provide assured protection against thrombogensis. These compositions should be capable of being applied satisfactorily and consistently to a variety of materials such as natural polymers and synthetic plastics and will result in complete coverage of a medical article substrate surface with an adhesive film coating.
In co-pending application U.S. Ser. No. 097,295, filed on Sept. 14, 1987, which is a continuation of U.S. Ser. No. 820,670 non-thrombogenic quaternary ammonium/heparin complexes were disclosed. These complexes were demonstrated as providing improved saline stability and biological activity over previously disclosed heparin materials. These disclosed complexes were alkylbenzyldimethyl ammonium cationic ions having the formula: ##STR2## Where R is a uniform alkyl group containing between 16 to 18 carbon atoms.
The present invention relates to additional alkylbenzyl ammonium/heparin complexes useful as coating composition having improved surface adhesion and anti-thrombogenic than heparin compositions heretofore known. These compositions have the distinct advantages of being relatively simple to prepare and easily applied as coatings to medical article surfaces.